1. Field
The invention relates in general to dispersing agents, and more particularly to dispersing agents for suspending medicaments in hydrofluoroalkane (HFA) propellants to be used in inhalation aerosols.
2. Description
There has long been realized a link between chlorofluorocarbons (CFCs) and the depletion of the ozone layer in the earth's atmosphere. Since the Montreal Protocol on Substances That Deplete the Ozone Layer, it has been agreed by most of the world's industrialized nations that the use of chlorofluorocarbons should be eliminated by the year 2000. Recently, parties to the Montreal Protocol voted to advance the deadline for phase out of CFCs to Jan. 1, 1996. Accordingly, there is an ongoing search for non-chlorofluorocarbon propellants.
Hydrofluoroalkanes (HFAs) are one group of aerosol propellants, and ttFA-134a (1,1,1,2-tetrafluoroethane) and HFA-227 (1,1,1,2,3,3,3-heptafiuoropropane) have been identified for possible use as replacement propellants in medicament containing aerosols. Unfortunately, neither HFA-134a nor HFA-227 effectively interacts with the dispersing agents currently utilized in pressurized meter dose inhalers (MDIs). Thus, there exists a chasm in adapting these propellants for use in MDIs.
European Patent Publication Numbers 0 499 344 and 0 372 777, the contents of which are herein incorporated by reference, describe aerosol formulations comprising a medicament, HFA-134a, a surfactant, and at least one compound or a co-solvent having a higher polarity than HFA-134a. Surfactants discussed as acceptable in these publications are sorbitan trifoliate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, polyethylene (20) sorbitan monooleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, oleic acid, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl, oleate, ethyloleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol 400, cetyl pyridinium chloride, olive oil, glyceryl monolaurate, corn oil, cotton seed oil, and sunflower seed oil. Such surfactants are also identified in International Publication No. WO 91/04011, the contents of which are herein incorporated by reference.
In another attempt to achieve satisfactory dispersion of a medicament in HFA-134a, the medicament was precoated with a surfactant prior to admixing with the HFA-134a propellant. In particular, micronized beclomethasone dipropionate was coated with Epikuron 200.
In World Patent Publication No. WO 92/00061, the contents of which are herein incorporated by reference, a hydrofluorocarbon propellant was used together with a polyethyloxylated surfactant. Using this surfactant, the formulation was made sufficiently stable without the need for additional solvents.
The present invention provides dispersing agents suitable for suspending medicaments in hydrofluoroalkane compositions. The subject dispersing agents are superior in these properties to those known in the art. Additionally, these dispersing agents provide the advantage of not requiring a co-solvent such as alcohol, thus eliminating the possibility of adverse interaction of alcohol with certain classes of medicaments.
The subject invention fulfills this need through the use of compounds which are generally regarded as safe (GRAS).